Method for the prevention and treatment of cachexia and anorexia

ABSTRACT

The present invention relates to methods and nutritional compositions for the prevention and treatment of cachexia and anorexia. The methods of the invention comprise administering a composition comprising effective amounts of ω-3 fatty acids such as alpha-linolenic acid, stearidonic acid, eicosapentaenoic acid, docosapentaenoic acid, docosahexaenoic acid or mixtures thereof; of branched-chain amino acids valine, leucine, isoleucine or mixtures thereof; with or without reduced levels of tryptophan and 5-hydroxytryptophan; and of antioxidant system selected from the group comprising beta-carotene, vitamin C, vitamin E, selenium, or mixtures thereof.

This application is a continuation-in-part of prior application Ser. No.08/635,179 filed Apr. 25, 1996, now abandoned which is herebyincorporated by reference.

The present invention relates to methods and nutritional compositionsfor the prevention and treatment of cancer cachexia and anorexia. In thepractice of the present invention patients are enterally administeredω-3 fatty acids including, but not limited to alpha-linolenic (18:3ω-3), stearidonic (18:4 ω-3), eicosapentaenoic (20:5 ω-3),docosapentaenoic (22:5 ω-3), and docosahexaenoic (22:6 ω-3), incombination with antioxidants including, but not limited to,beta-carotene, vitamin C, vitamin E, selenium, or mixtures thereof; asource of amino-nitrogen with high levels of branched-chain amino acidsincluding valine, leucine, isoleucine, and with or without reducedlevels of tryptophan and 5-hydroxytryptophan.

BACKGROUND

Cancer cachexia is a syndrome characterized by anorexia, weight loss,premature satiety, asthenia, loss of lean body mass, and multiple organdysfunction. The majority of patients with cancer whose diseaseprogresses to metastatic disease develop cachexia during their treatmentprogram and the cachexia contributes to their deaths. The frequency ofweight loss in cancer patients ranges from 40% for patients with breastcancer, acute myelocytic leukemia, and sarcoma to more than 80% inpatients with carcinoma of the pancreas and stomach. About 60% ofpatients with carcinomas of the lung, colon or prostate have experiencedweight loss prior to beginning chemotherapy. Although the relationshipbetween pretreatment malnutrition (weight loss) and adverse outcome isestablished, no consistent relationship has been demonstrated betweenthe development of cachexia and tumor size, disease stage, and type orduration of the malignancy. Development of cachexia in the cancerpatient is not caused simply by increased energy expenditure by the hostor by the tumor. The malignant cachexia is partially related to reducedcaloric intake.

Cancer cachexia is not simply a local effect of the tumor. Alterationsin protein, fat, and carbohydrate metabolism occur commonly. Forexample, abnormalities in carbohydrate metabolism include increasedrates of total glucose turnover, increased hepatic gluconeogenesis,glucose intolerance and elevated glucose levels. Increased lipolysis,increased free fatty acid and glycerol turnover, hyperlipidemia, andreduced lipoprotein lipase activity are frequently noted. The weightloss associated with cancer cachexia is caused not only by a reductionin body fat stores but also by a reduction in total body protein mass,with extensive skeletal muscle wasting. Increased protein turnover andpoorly regulated amino acid oxidation may also be important. Presence ofhost-derived factors produced in response to the cancer have beenimplicated as causative agents of cachexia, e.g., tumor necrosisfactor-α (TNF) or cachectin, interleukin-1 (IL-1), IL-6,gamma-interferon (IFN), and prostaglandins (PGs) (e.g., PGE₂).

Anorexia, with progressive depletion of body stores leading to thecachectic state, is observed in 50% of cancer-bearing patients.Different mechanisms proposed to explain the pathogenesis of anorexiainclude: (i) increased production of cytokines such as TNF and IL-1, and(ii) increased serotoninergic activity within the central nervous systemsecondary to enhanced availability to the brain of its precursor,tryptophan. Dickerson, J. W. T. et al., 1976, J. Neurochem 27: 1245-1247have suggested that diets should be selected to keep the ratio of plasmatryptophan to the sum of neutral amino acids constant. Cangiano, C., etal., 1994, Anticancer Res. 14: 1451-1456 has also disclosed that a closerelationship between plasma free tryptophan concentration and anorexiain cancer patients supports the serotoninergic system activity in thepathogenesis of cancer anorexia.

Cancer is characterized primarily by an increase in the number ofabnormal cells derived from a given normal tissue, invasion of adjacenttissues by these abnormal cells, and lymphatic or blood-borne spread ofmalignant cells to regional lymph nodes and to distant metastatic sites.Clinical data and molecular biologic studies indicate that cancer is amulti-step process that begins with minor preneoplastic changes, whichmay under certain conditions progress to neoplasia causing metaboliceffects such as cachexia.

Tumor cells differ from normal cells in their metabolism of fat in thattumor cells consume short-chain and medium-chain fatty acids poorly. Forexample, tumor-bearing mice fed a diet rich in medium-chaintriglycerides had less weight loss with a marked reduction in tumor sizecompared with animals fed long-chain triglycerides. Moreover, there havebeen problems reported with the use of high levels of medium-chaintriglycerides and use of structured lipids has been suggested in sometotal parenteral nutrition formulas. Moreover, these structured lipidsdo not provide the same benefits if administered enterally. U.S. Pat.Nos. 4,906,664 and 5,081,105 disclose the use of certain structuredlipids in the treatment of cancer. Preparations for enteral nourishmentincluding varying ratios of ω-6 to ω-3 (2.1:1-3.0:1) have also been usedin oncologic patients. However, these preparations used proportionatelylarger amounts of ω-6 to ω-3 fatty acids. Furthermore, thesepreparations did not include additional amounts of branched-chain aminoacids and antioxidants as set forth in the present invention. The use ofthe polyunsaturated fatty acid eicosapentaenoic acid is suggested forthe treatment of cachexia by inhibiting lipolytic activity of lipolyticagents in body fluids and the activity of the enzymeguanidino-benzoatase. See Tisdale, M. J., and Beck, A., U.S. Pat. No.5,457,130, issued Oct. 10, 1995; and Tisdale, et al. Cancer Research 50:5022-5026 (August 1990). However, the product taught by Tisdale was in asolid dosage form, requiring an already ill patient to swallow 12-16capsules per day. This method had serious drawbacks, includingdifficulty in swallowing, belching, and bad odor.

Thus, the prevention and/or treatment of cachexia and anorexia remain afrustrating problem. Both animal and human studies suggest thatnutritional support is largely ineffective in repleting lean body massin the cancer-bearing host. Randomized trials exploring the usefulnessof total parenteral nutrition (TPN) support as an adjunct to cytotoxicantineoplastic therapy have demonstrated little improvement in treatmentresults. See for example Brennan, M. F., and Burt, M. E., 1981, CancerTreatment Reports 65 (Suppl. 5): 67-68. This, along with a cleardemonstration that TPN can stimulate tumor growth in animals suggeststhe routine use of TPN in cancer treatment is not justified. Kisner, D.L., 1981, Cancer Treatment Reports 65 (Suppl. 5): 1-2.

Long chain fatty acid bio-pathways and physiological actions arediscussed in U.S. Pat. No. 5,223,285 to DeMichele, et al., the entirelyof which is incorporated herein by reference.

Also of interest is U.S. Pat. No. 5,444,054 to Garleb, et al. and arelated U.S. Pat. No. 5,780,451 (allowed application Ser. No.08/221,349). These documents describe compositions and methods useful inthe treatment of ulcerative colitis. Such compositions include a proteinsource that can be intact or hydrolyzed proteins of high biologicalvalue (col. 21); an indigestible oligosaccharide such asfructooligosaccharide; and a lipid blend containing a relatively highproportion of eicosapentaneoic acid, which contributes to a relativelyhigh ω-3 to ω-6 fatty acid ratio.

SUMMARY OF THE INVENTION

The methods of the invention generally comprise inhibiting metabolic andcytokine associated features of cachexia in an individual byadministering a nutritional composition comprising an effective amountof ω-3 fatty acids including, but not limited to alpha-linolenic acid,stearidonic acid, eicosapentaenoic acid, docosapentaenoic acid anddocosahexaenoic acid, alone or in combination with each other. Theinvention also relates to administering a nutritional compositioncomprising effective amounts of branched-chain amino acids, valine,leucine, isoleucine, or mixtures thereof, and with or without a reducedamount of tryptophan and hydroxytryptophan. The invention furtherprovides a method of reducing oxidative damage and anti-cancerdrug-induced immunosuppression in a cancer patient by administering anutritional composition comprising effective amounts of antioxidantsincluding, but not limited to beta-carotene, vitamin C, vitamin E,selenium, or mixtures thereof.

In one aspect, the invention provides a method of preventing the onsetof cachexia and/or anorexia, or treating existing cachexia and/oranorexia in a human comprising enterally administering to the human atleast:

(a) an oil blend containing ω-6 fatty acids and at least 450 mg of ω-3fatty acids, the weight ratio of ω-6 fatty acids to ω-3 fatty acidsbeing from about 0.1 to about 3.0; and

(b) a source of amino-nitrogen wherein 15% to 50% by weight of the aminoacids of said source of amino-nitrogen are branched-chain amino acids;and

(c) an antioxidant component comprised of at least one nutrient selectedfrom the group comprising beta-carotene, vitamin C, vitamin E, selenium,or mixtures thereof.

These components may be administered in a single composition or inseparate vehicles. Preferably, about 15% to about 25% of theamino-nitrogen is provided by branched-chain amino acids; mostpreferably, about 20%. It is also preferred that the source of aminonitrogen provides tryptophan in an amount of less than about 5.0% byweight of the total amount of the amino acids of said source ofamino-nitrogen; more preferably at a level of less than 3% by weight.

In another aspect, the invention provides a method of preventing theonset of anorexia or of treating existing anorexia in a human comprisingadministering to the human a nutritional composition comprisingamino-nitrogen wherein about 5 to 25 grams of branched-chain amino acidsselected from valine, leucine, isoleucine, or mixtures thereof arepresent in an amount from about 15% to about 50% by weight, preferablyabout 15-25%, of the total amount of amino-nitrogen present in saidnutritional composition, and wherein tryptophan in an amount not greaterthan about 5.0% by weight of the total amount of amino acids is presentin said composition and wherein ω-6 and ω-3 fatty acids are present at aweight ratio of from about 0.1 to about 3.0 and at least one antioxidantis present in the nutritional composition.

There is further disclosed a method for preventing immunosuppression ina human comprising administering to the human a liquid nutritionalcomposition comprising:

(a) an oil blend containing ω-6 and ω-3 fatty acids, the weight ratioω-6 fatty acids to ω-3 fatty acids being about from 0.1 to about 3.0;and

(b) an antioxidant component comprising about 2,500 to about 6,500micrograms per liter beta-carotene, about 250 to about 1,000 milligramsper liter vitamin C, about 100 to about 500 I.U. per liter vitamin E,and about 75 to about 125 mcg per liter selenium.

There is also disclosed a method of enhancing the transport and efficacyof anticancer drugs in a human having a cancerous condition comprisingadministering to the human a nutritional composition comprising an oilblend containing ω-6 and ω-3 fatty acids, the weight ratio of total ω-6fatty acids to ω-3 fatty acids being from about 0.1 to about 3.0.

In another aspect, the invention provides a liquid nutritionalcomposition comprising per liter:

(a) at least 0.45 gm (450 mg) of ω-3 fatty acids and wherein the weightratio of ω-6 fatty acids to ω-3 fatty acids is from about 0.1 to about3.0;

(b) at least 50 grams of a source of amino-nitrogen wherein 15 to 50% byweight of the amino-nitrogen is branched-chain amino acids and whereintryptophan is present in an amount less than about 5.0% by weight of thetotal amino-nitrogen; and

(c) at least 1 gram of an antioxidant system comprising beta-carotene,vitamin C, vitamin E and selenium.

Generally, such compositions provide much higher levels of the ω-3 fattyacids: preferably from about 1.0 gm to about 100 gm per liter; morepreferably, from about 5.0 gm to about 10 gm per liter. Similarly, it ispreferred that about 15-25% (typically about 20%) by weight of thesource of amino-nitrogen is branched-chain amino acids.

The various methods according to the present invention may beaccomplished by feeding a single composition that contains all thecomponents of the invention (ω-6 to ω-3 oil, branched-chain amino acidsand antioxidant system) or each component may be fed individually.Further, these methods may be accomplished through the consumption ofpills or capsules that contain the elements of the claimed invention. Inone embodiment of the invention, a nutritional liquid formulationcontaining all the elements of the invention is contemplated except forthe branched-chain amino acids which may be consumed in the form of apill or tablet.

In yet another co-embodiment of the invention, a liquid nutritionalproduct contains all the elements of the composition, wherein thebranched-chain amino acids are dispersed within the liquid in the formof microcapsules. This administration of the branched-chain amino acidsin the form of capsules, tablets, pills and/or microcapsules isadvantageous since the organoleptic or taste properties of the aminoacids are very objectionable.

In contrast to the prior art, the nutritional composition of the presentinvention is not restricted to correcting metabolism of just onenutrient class at a time, such as lipids or amino acids. Instead, apreferred nutritional multinutrient composition comprises a balancedformulation containing ω-3 fatty acids, antioxidants, branched-chainamino acids, and with or without a reduced level of tryptophan and5-hydroxytryptophan. Such a composition can demonstrate stronginhibition of cachexia and anorexia associated with a variety ofdifferent cancers (disease states).

In yet another embodiment, the methods further optionally compriseadministering the nutritional composition in combination with cancerchemotherapeutic agents, including but not limited to, 5-fluorouracil,mitomycin-C, adriamycin, chloroethyl nitrosoureas and methotrexate, toimprove the transport of the drug into the target cancer cells andultimately the efficacy of the anticancer agent.

The Examples presented below exemplify the use according to the methodsof the invention of ω-3 fatty acids, antioxidants, branched-chain aminoacids with or without a reduced level of tryptophan in nutritionaltherapy of cachexia and anorexia in human patients suffering fromdifferent cancers, including, but not limited to, liver, breast, lung,prostate, gastrointestinal and pancreatic cancer.

DETAILED DESCRIPTION OF THE INVENTION

"Cachexia" refers to a state of general ill health and malnutrition. Itis often associated with and induced by malignant cancer, and ischaracterized by loss of appetite, loss of body mass, especially leanbody mass, and muscle wasting.

"Anorexia" refers simply to a loss of appetite, whether brought on bymedical or psychological factors. Anorexia is often closely associatedwith, and generally contributes to, the cachexia seen in patients withadvanced cancers.

"Fatty acids" refer to a family of carboxylic acids having a hydrocarbonchain, generally from about 12 to 24 carbons long. When unsaturated(having a double bond) at least one point in the hydrocarbon chain, suchfatty acids are designated by the position of the first double bond. ω-3fatty acids have a first double bond at the third carbon from the methylend of the chain; and include, but are not limited to, α-linolenic acid,stearidonic acid, eicosapentaenoic acid ("EPA"), docosapentaenoic acidand docosahexaenoic acid ("DHA") and the like. ω-6 fatty acids have afirst double bond at the sixth carbon from the methyl end of the chain;and include, but are not limited to, linoleic acid, γ-linolenic acid,arachidonic acid ("AA"), and the like. The ratio of ω-6 fatty acids toω-3 fatty acids is simply the ratio of the total amounts (usuallyexpressed as weight) of each type.

Branched-chain amino acids are amino acids that have a fork or branch inthe side chain. These include primarily those having a carbon-carbonbranch, i.e. valine, leucine and isoleucine; but may also include othertypes of branches.

"Nutritional matrix" as used herein refers to a delivery vehicle thatcontains fats, amino nitrogen and carbohydrates and provides some or allof the nutritional support for a patient in the recommended dailyamounts. Frequently a nutritional matrix will contain vitamins,minerals, trace minerals and the like to provide balanced nutrition.

"Cytokines" as used herein refer to the causative agents of cachexia inthe cancer patient, produced by the individual in response to thepresence of cancer, and include, but are not limited to, tumor necrosisfactor (TNF) or cachectin, interleukin-1 (IL-1), IL-6 andgamma-interferon (IFN). TNF is produced by the macrophages in responseto nonspecific stimuli including cancer, infection, trauma and stress.The mechanism of action in cancer cachexia involves an immune responseto the tumor with the production of cytokines, which not only mediatetumor lysis but also the metabolic changes seen in cancer cachexiathrough specific TNF receptors and/or via the induction of othercytokine receptors.

While not intending the invention to be limited to any particular theoryof operation, applicants describe below a probable mechanism. A mode ofaction of cytokines is mediated via interactions with receptors on theplasma membrane. This is typically defined as a "signal transductionevent." In general, a cytokine receptor consists of an extracellulardomain, a transmembrane region spanning the phospholipid bilayer of theplasma membrane, and an intracellular domain having either enzymaticactivity or binding other molecules, so that a signal is deliveredinside the cell in response to the cytokine ligand interaction. Thesignal transduction mechanisms involve second messengers, includingphospholipases, adenylate cyclase and cyclic AMP, inositol phosphates,diacylglycerols and protein kinase C. More particularly, phospholipaseA2 generates arachidonic acid, a precursor of dienoic prostaglandins,thromboxanes, prostacyclin and leukotrienes of the 4 series.

Cytokines such as TNF and IL-1 stimulate production of arachidonic acidmetabolites which are important to their inflammatory and tissuedamaging actions and are responsible for immunosuppression in general,and in exacerbating some paraneoplastic conditions including metabolicchanges seen in cancer cachexia.

The invention is based, in part, on a method of inhibiting signaltransduction and cytokine activity using nutritional compositionscomprising high levels of ω-3 fatty acids, in particular, of the longchain (e.g. 20 or more carbons) ω-3 fatty acids, eicosapentaenoic (EPA)and docosahexaenoic (DHA).

Since administration of EPA and DHA results in a reduction ofarachidonic acid in membrane phospholipids, such an effect not onlydiminishes the supply of arachidonic acid as a precursor for the dienoiceicosanoids but also inhibits their production through competitiveinhibition by EPA. The cyclooxygenase and lipoxygenase metabolites ofEPA have attenuated activity. Furthermore, ω-3 fatty acids,alpha-linolenic and stearidonic can be converted throughelongation/desaturation to EPA; and similarly, DHA can be retroconvertedto EPA. Thus, the methods of invention comprise methods of inhibitingcytokine activity (e.g., TNF, IL-1) and cancer cachexia by interferingwith signal transduction at the receptor level and inhibitingarachidonic acid metabolism.

Incorporation of ω-3 fatty acids in membrane phospholipids not onlyalters the activity of membrane-associated enzymes (e.g., phospholipaseA2) but also alters the balance between constituent saturated andunsaturated fatty acids and regulation of membrane fluidity, facilitatesthe transport of anticancer drugs into the cancer cells and thusenhances the efficacy of the drugs. Alberts, A. W., et al., 1978,Biochim. Biophys. Acta 509:239-250. In addition, the inhibition ofarachidonic acid metabolism results in prevention and/or reversal ofimmunosuppression by reducing the production of prostaglandins andleukotrienes (PGE2 and LTB4), which are immunosuppressive.

The invention also provides a method of reducing the concentration ofbrain tryptophan and serotonin to prevent or inhibit premature satietyand cancer cachexia and/or anorexia in a cancer patient in whom theprevention and treatment of cancer anorexia is desired by administeringeffective amounts of branched-chain amino acids, valine, leucine,isoleucine, or mixtures thereof, and with or without a reduced amount oftryptophan.

The methods and compositions of the invention provide a method ofmanipulating the concentration of brain tryptophan by: (i) increasingthe branched-chain amino acids, which provide competition for tryptophanfor penetration across the blood-brain barrier; and (ii) reduced levelsof tryptophan and 5-hydroxytryptophan in relation to branched-chainamino acids in the nutritional composition of the invention. Such anintervention can increase appetite and thus prevent and/or treat canceranorexia.

The methods and compositions of the invention also provide a method ofreducing the risk or progression of certain symptoms of cancer, such ascancer cachexia and anorexia by administering antioxidant nutrientsincluding, but not limited to, beta-carotene, vitamin C, vitamin E,selenium, or mixtures thereof. Epidemiological evidence indicates that acombination of beta-carotene, vitamin E and selenium can effect areduction in cancer risk in some populations. Blot, N. J. et al., 1993,J. Natl. Cancer Inst. 85: 1483-1492. Furthermore, vitamin E is added tosatisfy any additional requirements as a result of a higher intake ofω-3 polyunsaturated fatty acids. By the administration of theantioxidant nutrients of the invention to cancer patients havingcachexia and whose immune system has been depressed on account ofchemotherapy and/or oxidative burden, improvements in the nutritionalstatus, as well as prevention and treatment of immunosuppression andcachexia can be achieved.

Nutritional support in the cancer patient can be categorized as (i)supportive, in which nutrition support is instituted to preventnutrition deterioration in the adequately nourished patient or torehabilitate the depleted patient before definitive therapy; (ii)adjunctive, in which nutrition support plays an integral role in thetherapeutic plan; and (iii) definitive, in which aggressive nutritionsupport is required for the patient's existence. The routes forproviding nutrition support include an oral diet, tube feeding andperipheral or total parenteral nutrition. The preferred embodiment fornutritional methods and compositions of the invention is by the oralroute.

An alternate to oral feeding is tube feeding by means of nasogastric,nasoduodenal, esophagostomy, gastrostomy, or jejunostomy tubes.

A typical nutritional composition useful in the method of this inventionwill have a caloric distribution as follows: about 12 to 24% (target21%) from a source of amino-nitrogen, about 40 to 65% (target 61%) fromcarbohydrate and about 10 to 35% (target 18%) from fat. Moreparticularly, the oil blend may comprise approximately 30% of ω-3 fattyacids, preferably largely consisting of eicosapentaenoic acid anddocosahexaenoic acid. Dietary oils used in the preparation of thenutritional composition generally contain ω-3 fatty acids in thetriglyceride form and include, but are not limited to canola, mediumchain triglycerides, fish, soybean, soy lecithin, corn, safflower,sunflower, high-oleic sunflower, high-oleic safflower, olive, borage,black currant, evening primrose and flaxseed oil. Table 1 sets forthboth preferred amounts and ranges for an oil blend useful in theinvention. Specifically, the weight ratio of ω-6 fatty acids to ω-3fatty acids in the lipid blend according to the invention is about 0.1to 3.0. The daily delivery of ω-3 fatty acids should be at least 450 mgand may vary depending on body weight, sex, age and medical condition ofthe individual. As mentioned, higher levels are desired for adult humanconsumption: for example, from about 0.5 to 50 gm daily, more preferablyfrom about 2.5 to 5 gm daily.

                  TABLE 1                                                         ______________________________________                                        OIL BLEND                                                                     (% total weight of lipid blend)                                               OIL          PREFERRED  RANGE                                                 ______________________________________                                        Canola       9.3%        5.0-40.0%                                            MCT          16.2%      10.0-50.0%                                            Fish         65.0%      25.0-80.0%                                            Soybean      5.5%        3.0-30.0%                                            Soy lecithin 4.0%       2.0-6.0%                                              ______________________________________                                    

Table 2 presents the fatty acid profile of an exemplary oil blend usefulin the present invention. The weight ratio of the total ω-6 fatty acidsto the total ω-3 fatty acids in this embodiment is 0.26 to 1 which iswithin the claimed range for this invention.

                  TABLE 2                                                         ______________________________________                                        FATTY ACID PROFILE                                                            (% of total fatty acids by weight)                                            OIL                %                                                          ______________________________________                                        Caproic (6:0)      0.53                                                       Capyrlic (8:0)     10.35                                                      Capric (10:0)      7.16                                                       Lauric (12:0)      0.29                                                       Myristic (14:0)    3.53                                                       Palmitic (16:0)    7.41                                                       Palmitoleic (16:1ω7)                                                                       5.73                                                       Stearic (18:0)     1.39                                                       Oleic (18:1ω9)                                                                             15.23                                                      Linoleic (18:2ω6)                                                                          7.21                                                       Gamma-linoleic (18:3ω6)                                                                    0.21                                                       Alpha-linoleic (18:3ω3)                                                                    2.21                                                       Stearidonic (18:4ω3)                                                                       2.40                                                       Arachidic (20:0)   0.13                                                       Eicosenoic (20:1ω9)                                                                        0.74                                                       Arachidonic (20:4ω6)                                                                       0.87                                                       Eicosapentaenoic (20:5ω3)                                                                  17.14                                                      Erucic (22:1ω9)                                                                            0.17                                                       Docosapentaenoic (22:5ω3)                                                                  2.08                                                       Docosahexaenoic (22:6ω3)                                                                   7.73                                                       Nervonic (24:1ω9)                                                                          0.14                                                       Others             7.35                                                       Total              100.00                                                     ______________________________________                                    

                  TABLE 3:                                                        ______________________________________                                        LIPID BLEND CHARACTERISTICS                                                   ______________________________________                                        % ω-3 fatty acids                                                                             30.51                                                   % ω-6 fatty acids                                                                             9.67                                                    % ω-9 fatty acids                                                                             15.28                                                   % saturated fatty acids                                                                             27.07                                                   % monounsaturated fatty acids                                                                       19.33                                                   % polyunsaturated fatty acids                                                                       40.17                                                   ω-6/ω-3 ratio                                                                           0.32                                                    18:2ω6/18:3ω3 ratio                                                                     4.26                                                    18:3ω3, % total energy                                                                        0.33                                                    18:2ω6, % total energy                                                                        1.41                                                    18:1ω9, % total energy                                                                        2.42                                                    PUFAs, % total calories                                                                             7.23                                                    saturated fatty acids, % total calories                                                             4.87                                                    EPA (20:5ω3) per 8 oz container, g                                                            1.09                                                    DHA (22:6ω3) per 8 oz container, g                                                            0.46                                                    ______________________________________                                    

Table 3 (above) sets forth selected characteristics of an oil blenduseful in the method of this invention. However, it will be realizedthat the characteristics may vary among other formulas useful for thisinvention, depending on the specific oils added and the ratios in whichthey are used.

An amino acid profile for a nutritional composition useful in theinvention is presented in Table 4.

                  TABLE 4                                                         ______________________________________                                        AMINO ACID PROFILE                                                            Amino Acid     g/100 g Protein                                                ______________________________________                                        Aspartic Acid  7.08                                                           Threonine      4.34                                                           Serine         5.68                                                           Glutamic Acid  20.58                                                          Proline        10.55                                                          Glycine        1.81                                                           Alanine        3.04                                                           Valine         5.90                                                           Methionine     2.78                                                           Isoleucine     4.77                                                           Leucine        9.08                                                           Tyrosine       4.79                                                           Phenylalanine  4.96                                                           Histidine      2.67                                                           Lysine         7.27                                                           Arginine       3.15                                                           Tryptophan     0.99                                                           Cystine        0.56                                                           Total BCAA     19.75                                                          ______________________________________                                    

The total amount of branched-chain amino acids ("BCAA") useful in thepresent invention is about 15-50 g/100 g protein (i.e. percent),preferably about 15-25 g/100 g. Thus, an 8 oz container of thenutritional composition would contain up to about 8g BCAAs per 16 gramsof total protein. The daily delivery of BCAAs is about 5-26 g. In orderto deliver such a high amount of the BCMs, and because the BCMs impartan unpleasant taste, the nutritional composition may be accompanied by1-3 gelatin capsules containing BCAAs to provide the additional amountrequired above the inherent amount present in the liquid product. Thepreferred BCAAs are, but are not limited to, leucine, isoleucine andvaline, and are predominantly bitter in taste. Therefore, administeringthe additional BCAAs in encapsulated form avoids taste problems whichare encountered with the use of quantities greater than 20 g/100 gprotein of BCAAs in the liquid product. The microencapsulated BCAAs mayalso be mixed with taste masking compounds including, but not limitedto, polyphosphates, cyclodextrin (a cyclic glucose oligomer) andThaumatin (a proteinaceous intense sweetener).

A representative antioxidant profile useful in the method of theinvention is presented in Table 5 with range values and a preferredembodiment.

                  TABLE 5                                                         ______________________________________                                        ANTIOXIDANT PROFILE                                                           Antioxidant  Preferred  Range                                                 ______________________________________                                        Beta-carotene                                                                              5,000   μg/L                                                                              2,500-6,500 μg/L                               Vitamin E    300     IU/L   100-500 IU/L                                      Vitamin C    650     mg/L    250-1,000 mg/L                                   Selenium     90      μg/L                                                                              78.8-125 μg/L                                  ______________________________________                                    

The overall nutrient profile of this example is set forth in Table 6. Ina specific embodiment of this invention, the nutritional productprovides at least 100% of the U.S. RDA for vitamins and minerals in 1184mL (five 8 fluid ounce servings), which would provide 1184 kcal per day.

If used as a sole source of nutrition, and assuming a 2000 kcal diet,between 8 and 9 servings (237 mL; 8 fluid ounces) of this illustrativeformulation would be required. However, as seen from example IV below,there is benefit derived from supplementation with as few as twoservings per day. Thus a minimum daily amount of long chain ω-3 fattyacids is preferably about 3 grams, calculated as (1.06 g EPA+0.46 g DHA)times 2 8 oz servings. Of course, if more servings are consumed toprovide additional calories, more ω-3 fatty acids will be administered,up to a practical maximum of about 14 grams per day (about 9 servings atsame fatty acid levels). Levels of the fatty acids, antioxidants and/orsource of amino nitrogen on a per liter basis are not crucial, except tothe extent that a reasonable volume of fluid should supply therecommended daily amounts consistent with the invention. Determinationof a reasonable volume is easily within the ambit of those skilled inthe art, especially in view of the specific guidance found in theexamples.

                  TABLE 6                                                         ______________________________________                                        NUTRIENT PROFILE                                                              Nutrient             Qty/Liter                                                ______________________________________                                        Protein, g           67.40                                                    Fat, g               27.20                                                    Carbohydrate, g      207.00                                                   Total Dietary Fiber, g                                                                             10.70                                                    Indigestible Oligosaccharide (FOS), g                                                              12.40                                                    Gum Arabic, g        9.10                                                     Soy Polysaccharide, g                                                                              1.60                                                     Beta-carotene, μg 5000                                                     Vitamin A, IU        5500                                                     Vitamin D, IU        800.00                                                   *Vitamin E, IU       300.00                                                   Vitamin K, μg     135.00                                                   Vitamin C, mg        650.00                                                   Folic Acid μg     1900                                                     Thiamine, mg         6.50                                                     Riboflavin, mg       5.00                                                     Vitamin B.sub.6, mg  5.00                                                     Vitamin B.sub.12, μg                                                                            18.00                                                    Niacin, mg           40.00                                                    Choline, mg          525.00                                                   Biotin, μg        750.00                                                   Pantothenic Acid, mg 24.00                                                    Sodium, mg           1500                                                     Potassium, mg        2000                                                     Chloride, mg         1519                                                     Calcium, mg          1800                                                     Phosphorous, mg      1250                                                     Magnesium, mg        450.00                                                   Iodine, μg        175.00                                                   Copper, mg           2.61                                                     Zinc, mg             29.20                                                    Iron, mg             22.20                                                    Selenium, μg      90.00                                                    Chromium, μg      125.00                                                   Molybdenum, μg    206.00                                                   Carnitine, mg        150.00                                                   Taurine, mg          275.00                                                   Kcal/mL              1                                                        ______________________________________                                         *d-alpha-tocopherol (all natural form) or dlalpha-tocopherol acetate, or      combination of the two.                                                  

The following specific examples are set forth to illustrate variouspreferred embodiments of the invention but the scope of the invention isdefined by the appended claims.

EXAMPLE I

The specific list of materials for manufacturing the nutritional cancerproduct of this Example I is presented in Table 7. Of course, variouschanges in specific ingredients and quantities may be made withoutdeparting from the scope of the invention.

                  TABLE 7                                                         ______________________________________                                        LIST OF MATERIALS                                                             INGREDIENT               AMOUNT                                               ______________________________________                                        WATER                    31,605.21 kg                                         GUM ARABIC               437.84    kg                                         ULTRATRACE/TRACE MINERAL PREMIX                                                                        14.50     kg                                         ZINC SULFATE             2969.89   gm                                         FERROUS SULFATE          2856.50   gm                                         MANGANESE SULFATE        784.60    gm                                         CUPRIC SULFATE           423.11    gm                                         SODIUM MOLYBDATE         21.39     gm                                         CHROMIUM CHLORIDE        20.80     gm                                         SODIUM SELENITE          8.11      gm                                         CITRIC ACID              894.94    gm                                         SUCROSE (Carrier)        6520.67   gm                                         POTASSIUM CITRATE        50.00     kg                                         SODIUM CITRATE           95.00     kg                                         POTASSIUM IODIDE         9.00      gm                                         POTASSIUM CHLORIDE       91.00     kg                                         CORN SYRUP SOLIDS        5630.96   kg                                         MALTODEXTRIN             1407.52   kg                                         MAGNESIUM PHOSPHATE DIBASIC                                                                            131.00    kg                                         CALCIUM PHOSPHATE TRIBASIC                                                                             47.50     kg                                         (PREFERABLY MICRONIZED)                                                       CALCIUM CARBONATE        122.50    kg                                         SUGAR (SUCROSE)          852.77    kg                                         FRUCTOOLIGOSACCHARIDE    509.96    kg                                         MEDIUM CHAIN TRIGLYCERIDES                                                                             172.69    kg                                         (FRACTIONATED COCONUT OIL)                                                    CANOLA OIL               99.13     kg                                         SOY OIL                  58.63     kg                                         57% VITAMIN A PALMITATE  250.00    gm                                         2.5% VITAMIN D           35.00     gm                                         D-ALPHA-TOCOPHEROL ACETATE (R,R,R)                                                                     10.65     kg                                         PHYLLOQUINONE            6.50      gm                                         30% BETA-CAROTENE        824.00    gm                                         SOY LECITHIN             42.64     kg                                         SODIUM CASEINATE         1427.04   kg                                         PARTIALLY HYDROLYZED SODIUM                                                                            1427.04   kg                                         CASEINATE                                                                     SOY POLYSACCHARIDE       85.28     kg                                         75% WHEY PROTEIN CONCENTRATE                                                                           184.46    kg                                         REFINED DEODORIZED SARDINE OIL                                                                         692.87    kg                                         ASCORBIC ACID            37.08     kg                                         45% POTASSIUM HYDROXIDE  25.96     kg                                         TAURINE                  12.00     kg                                         WATER SOLUBLE VITAMIN PREMIX                                                                           4.50      kg                                         NIACINAMIDE              1688.60   gm                                         CALCIUM PANTOTHENATE     1092.24   gm                                         THIAMINE CHLORIDE HYDROCHLORIDE                                                                        278.78    gm                                         PYRIDOXINE HYDROCHLORIDE 268.34    gm                                         RIBOFLAVIN               217.87    gm                                         FOLIC ACID               37.82     gm                                         BIOTIN                   32.87     gm                                         CYANOCOBALAMIN           0.75      gm                                         DEXTROSE (Carrier)       882.74    gm                                         FOLIC ACID               43.50     gm                                         CHOLINE CHLORIDE         25.00     kg                                         L-CARNITINE              7.00      kg                                         ARTIFICIAL STRAWBERRY FLAVOR                                                                           31.75     kg                                         ARTIFICIAL CREAM FLAVOR  18.14     kg                                         FD & C Red Dye No. 3     1,220.16  gm                                         ______________________________________                                    

The liquid nutritional product of the present invention was manufacturedby preparing three slurries which are blended together, combined withrefined deodorized sardine oil, heat treated, standardized, packaged andsterilized. The process for manufacturing 45,360 kg (100,000 pounds) ofthe liquid nutritional product, using the List of Materials from Table7, is described in detail below.

A carbohydrate/mineral slurry is prepared by first heating about 6,260kg of water to a temperature in the range of about 71° C. to 77° C. withagitation. The gum arabic is then added to the water using a mixingapparatus. Next the ultratrace/trace mineral premix is added to thewater and dissolved by agitating the resultant solution for at least oneminute. The following minerals are then added, in the order listed, withhigh agitation: potassium citrate, sodium citrate, potassium iodide andpotassium chloride. The corn syrup solids (Grain Processing Corporation,Muscatine, Iowa, U.S.A. under the trade designation "Maltrin M-200") andmaltodextrin (Grain Processing Corporation, trade designation "MaltrinM-100") are then added to the slurry and the temperature of the slurryis maintained at about 71° C. with high agitation for at least about 20minutes.

Add magnesium phosphate dibasic, calcium phosphate tribasic, and calciumcarbonate to the slurry. Sugar (sucrose), and fructooligosaccharide(Golden Technologies Company, Golden, Colo., U.S.A. under the tradedesignation "Nutriflora-P- Fructo-oligosaccharide Powder (96%)") areadded to the slurry. The completed carbohydrate/mineral slurry is heldwith high agitation at a temperature in the range of about 60-66° C. fornot longer than 12 hours until it is blended with the other slurries.

An oil slurry is prepared by combining and heating the medium chaintriglycerides (fractionated coconut oil), canola oil and soy oil to atemperature in the range of about 32-43° C. with agitation. The 57%vitamin A palmitate, 2.5% vitamin D₃, D-alpha-tocopherol acetate (R,R,Rform; Distillation Products Industries, a division of Eastman KodakChemical Company, Rochester, N.Y. U.S.A. under the trade designation"Eastman Vitamin E 6-81 D-Alpha Tocopherol Acetate Concentrate"),phylloquinone and 30% beta-carotene are added to the slurry withagitation. The soy lecithin is then added to the slurry with agitation.The completed oil slurry is held under moderate agitation at atemperature in the range of about 32-43° C. for not longer than 12 hoursuntil it is blended with the other slurries.

A protein-and-fiber-in-water slurry is prepared by first heating about19,678 kg of water to a temperature in the range of about 60-63° C. withagitation. Sodium caseinate, partially hydrolyzed sodium caseinate(distributed by New Zealand Milk Products, Santa Rosa, Calif., U.S.A.under the trade name Alanate 167) and soy polysaccharide are blendedinto the slurry using a mixing apparatus. The temperature of the slurryis lowered to about 57-60° C. and then the 75% whey protein concentrateis added to the slurry using a mixing apparatus. The completedprotein-and-fiber-in-water slurry is held under agitation at atemperature in the range of about 54-60° C. for not longer than 2 hoursbefore being blended with the other slurries.

The oil slurry and the protein-and-fiber-in-water slurry are blendedtogether with agitation and the resultant blended slurry is maintainedat a temperature in the range of about 54-66° C. After waiting for atleast one minute the carbohydrate/mineral slurry is added to the blendedslurry from the preceding step with agitation and the resultant blendedslurry is maintained at a temperature in the range of about 54-66° C.The vessel which contained the carbohydrate/mineral slurry should berinsed with about 220 kg of water and the rinse water should be added tothe blended slurry. The refined deodorized sardine oil (distributed byMochida International Company, Limited, Shinjuku-ku, Tokyo, Japan underthe trade designation "50% Omega-3 marine oil EPA:DHA 28:12 with 0.8%mixed tocopherol as antioxidant") is then added to the slurry withagitation. (In a most preferred method of manufacture the sardine oilwould be slowly metered into the product as the blend passes through aconduit at a constant rate.) Preferably after at least 5 minutes the pHof the blended slurry is determined. If the pH of the blended slurry isbelow 6.55, it is adjusted with dilute potassium hydroxide to a pH of6.55 to 6.8.

After waiting a period of not less than one minute nor greater than two45 hours the blended slurry is subjected to deaeration,Ultra-High-Temperature (UHT) treatment, and homogenization, as describedbelow:

A. Use a positive pump for supplying the blended slurry for thisprocedure.

B. Heat the blended slurry to a temperature in the range of about 66-71°C.

C. Deaerate the blended slurry to 25.4-38.1 cm of Hg.

D. Emulsify the blended slurry at 61-75 Atmospheres.

E. Heat the blended slurry to a temperature in the range of about120-122° C. by passing it through a plate/coil heat exchanger with ahold time of approximately 10 seconds.

F. UHT heat the blended slurry to a temperature in the range of about144-147° C. with a hold time of approximately 5 seconds.

G. Reduce the temperature of the blended slurry to be in the range ofabout 120-122° C. by passing it through a flash cooler.

H. Reduce the temperature of the blended slurry to be in the range ofabout 71-82° C. by passing it through a plate/coil heat exchanger.

I. Homogenize the blended slurry at about 265 to 266 Atmospheres.

J. Pass the blended slurry through a hold tube for at least 16 secondsat a temperature in the range of about 74-85° C.

K. Cool the blended slurry to a temperature in the range of about 1-70°C. by passing it through a large heat exchanger.

Store the blended slurry at a temperature in the range of about 1-7° C.,preferably with agitation.

Preferably at this time appropriate analytical testing for qualitycontrol is conducted. Based on the test results an appropriate amount ofdilution water (10-38° C.) is added to the blended slurry withagitation.

A vitamin solution, a flavor and a color solution are preparedseparately and then added to the blended slurry.

The vitamin solution is prepared by heating about 394 kg of water to atemperature in the range of about 43-66° C. with agitation, andthereafter adding the following ingredients, in the order listed:Ascorbic Acid, 45% Potassium Hydroxide, Taurine, Water Soluble VitaminPremix, Folic Acid, Choline Chloride, and L-Carnitine. The vitaminsolution is then added to the blended slurry with agitation.

The flavor solution is prepared by adding the artificial strawberryflavor and artificial cream flavor to about 794 kg of water withagitation. A nutritional product according to the present invention hasbeen manufactured using an artificial strawberry flavor distributed byFirmenich Inc., Princeton, N.J., U.S.A. under the trade designation"Art. strawberry 57.883/A" and an artificial cream flavor distributed byFirmenich Inc. under the trade designation "Art Cream 59.200/A". Theflavor solution is then added to the blended slurry with agitation.

A color solution is prepared by adding the FD&C Red Dye No. 3 to about121 kg of water with agitation. The color solution is then added to theblended slurry with agitation.

If necessary, diluted potassium hydroxide is added to the blended slurrysuch that the product will have a pH in the range of 6.4 to 7.0 aftersterilization. The completed product is then placed in suitablecontainers and subjected to sterilization. Of course, if desired asepticprocessing could be employed.

The product made according to the procedure of this example contains theoil blend of Table 8, below, the the fatty acid properties of Tables 2and 3, and the amino acid profile of Table 4, all set forth above.

                  TABLE 8                                                         ______________________________________                                        OIL BLEND                                                                     (% total weight of lipid blend)                                               OIL          Percent Total Lipids                                             ______________________________________                                        Canola       9.3%                                                             MCT          16.2%                                                            Fish         65.0%                                                            Soybean      5.5%                                                             Soy lecithin 4.0%                                                             ______________________________________                                    

EXAMPLE II

The objective of this experiment was to evaluate the organolepticcharacteristics of nutritional composition of the invention fortified bythe addition of branched-chain amino acids incorporated at two differentlevels. To measure organoleptic properties, three taste standards,described in Table 9, were prepared to rank the bitter and sourintensity of the test compositions containing branched-chain aminoacids.

                  TABLE 9:                                                        ______________________________________                                        TASTE INTENSITY SCALE                                                                 Basic           Concentration*                                                                          Representative                              Standard                                                                              Taste  Intensity                                                                              by Weight Products                                    ______________________________________                                        1       Sour   1        0.05% Citric Acid                                                                       Milk Chocolate,                                                               Coffee                                                                        Whole Peanuts                               2       Bitter 1        0.05% Caffeine                                                                          Milk Chocolate                              3       Bitter 2        0.10% Caffeine                                                                          Beer                                        ______________________________________                                         *Aqueous solutions                                                       

Two test compositions (designated "high" and "low") were prepared byadding selected branched-chain amino acids ("BCAA") to the liquidnutritional composition of Example I. A control composition of Example Ithat did not contain the supplemental branched-chain amino acids wasalso evaluated for flavor characteristics. The specific amino acids andamounts added are given in Table 10. In both test compositions thebranched-chain amino acids did not completely disperse in thenutritional composition due to their hydrophobic nature, and smallclumps of branched-chain amino acids were visible in the matrix. Thetest compositions were evaluated and the results of the organoleptictest scoring are also set forth in Table 10.

                  TABLE 10                                                        ______________________________________                                        BRANCHED-CHAIN AMINO ACID FORTIFICATION                                                      "high" test                                                                           "low" test                                                                             control                                       ______________________________________                                        BCM in gm/237 mL serving                                                      valine           2.5       1.3      0                                         leucine          2.5       1.3      0                                         isoleucine       2.5       1.3      0                                         Total            7.5       3.9      0                                         TASTE TEST SCORE                                                              bitter           1.5 to 2  1.5      none                                      sour             0.5       0.5      none                                      ______________________________________                                    

Based on the results of this taste session, the evaluators collectivelyagreed that the bitter and sour flavor notes attributed to thebranched-chain amino acids are less than ideal for a ready-to-use oralnutritional composition. Thus, in one embodiment of this invention, anyadditional branched-chain amino acids are supplied to patient in theform of a pill or capsule distinct from the liquid nutritional of theinvention.

EXAMPLE III

The effect of nutritional intervention with ω-3 fatty acids,branched-chain amino acids and antioxidants in the nutritionalcompositions of the invention, on prevention and treatment of cachexiacan be monitored by any of the methods known to one skilled in the art,including but not limited to measuring: (i) food intake, body weight andanthropometric measurements; (ii) serum levels of lipids, fatty acids,amino acids and antioxidants; (iii) levels of serologic markers whereappropriate, e.g., carcinoembryonic (CEA) antigens, serotonin,C-reactive protein, TNF and IL-1; (iv) changes in the morphology oftumors using techniques such as computed tomographic (CT) scan,ultrasonography, magnetic resonance imaging (MRI) and position emissiontomography (PET).

Patients with hepatocellular carcinoma showing symptoms of cachexia areprovided with the nutritional product of the invention with small,frequent feedings after surgical resection if the liver tumor islocalized and small, or along with a regimen of chemotherapy. The liverfunctions and characteristics of the hepatic carcinomas are tested byprocedures known in the art.

The daily nutritional management of liver cancer, therefore, includesadministration of 2 to 4 containers of 8 ounce servings (237 mL) of thenutritional composition providing a daily amount of: (i) combined EPAand DHA in the range of 3 to 6 g, with the preferred dosage being about3 g; (ii) branched-chain amino acids in the range of 5 to 25 g, with thepreferred dosage being about 10-15 g branched-chain amino acids; and(iii) vitamin C in the range of 125 to 500 mg, with the preferred dosagebeing about 300 mg vitamin C; (iv) vitamin E in the range of 50 to 250IU, with the preferred dosage being about 150 IU vitamin E; (v)beta-carotene in the range of 1250 to 3250 μg, with the preferred dosagebeing about 2500 beta-carotene μg; (vi) selenium in the range of 40 to60 μg, with the preferred dosage being about 45 μg selenium. The effectof nutritional intervention on cancer cachexia and anorexia aremonitored at monthly intervals (or as recommended in the clinicalfollow-up) as known in the art, and depending on the results obtained,the therapeutic regimen is developed to maintain and/or boost the weightgain by the patient, with the ultimate goal of achieving tumorregression and complete eradication of cancer cells.

For the underweight breast cancer patient on adjuvant chemotherapy,administration of the nutritional composition of the invention isstarted any time after surgery. The nutritional composition used inbreast cancer patients is designed to maintain an adequate intake inspite of nausea, mucositis, and other side effects of chemotherapy.Patients receiving radiation therapy for breast cancer receive effectiveamounts of the nutritional composition to promote maintenance and repairof body tissue. The therapeutic and/or prophylactic regimens used inbreast cancer patients are the same as those described in Section 6above for patients recovering from hepatocellular carcinoma. Theprocedures of monitoring the patient under clinical evaluation forprevention and treatment of cachexia and anorexia in breast cancer areknown in the art.

EXAMPLE IV

A pilot study was conducted to assess the effectiveness of a specificformula in ameliorating the cachexia of cancer patients. The formula ofExample I was prepared. In addition to other nutrients, it contained(per two 237 mL servings) the long-chain ω-3 fatty acids, thefructooligosaccharide ("FOS") and the antioxidant system specified inTable 10.

                  TABLE 10                                                        ______________________________________                                        TRIAL PRODUCT                                                                 Ingredient     Amount per 2 × 237 mL servings                           ______________________________________                                        EPA ω3   2.0          gm                                                DHA ω-3  0.92         gm                                                fructooligosaccharide                                                                        5.8          gm                                                beta carotene  2.8          mg                                                vitamin G      300.         mg                                                vitamin E      150.         IU                                                selenium       58.          mcg                                               ______________________________________                                    

In the pilot clinical trial of this example, ten patients withpancreatic cancer were evaluated. These patients were cachectic andlosing weight at a mean rate of 0.86 kg per week over an average of 22weeks (range: 11 to 56 weeks) prior to the trial. Over a three weektrial period, patients consumed an average of two 237 mL (8 fluidounces) servings per day as a supplement to their diets. After the trialperiod the group demonstrated a mean increase in weight of 2.1 kg (upfrom baseline), which translates to a mean weekly weight gain of 0.7 kg(See Table 11).

                  TABLE 11                                                        ______________________________________                                        Patients' Age, Gender and Weight Status                                                     Mean Weekly                                                                              Base- Weight                                               Patient Wt (kg)    line  after  Mean Weekly                                   Age and Change up  weight                                                                              three week                                                                           Wt change                               Patient                                                                             Gender  to Baseline                                                                              (kg)  trial (kg)                                                                           during trial                            ______________________________________                                        1     56f     -0.4       51    51.75  0.25                                    2     64m     -1.2       67    na     na                                      3     70m     -0.5       61    67.5   2.17                                    4     60m     -0.9       43    44     0.33                                    5     53f     -1.4       90    90.5   0.17                                    6     51f     -1.2       44.5  45.5   0.33                                    7     67m     -0.6       57    58     0.33                                    8     75f     -0.8       55    59     1.33                                    9     57m     -0.6       69    na     na                                      10    53f     -1         57.5  na     na                                      Mean           -0.86                  0.7                                     ______________________________________                                    

In addition, much of the weight gained was lean body mass. The groupdemonstrated a mean increase in lean body mass of 2.1% and a decrease inC-reactive protein ("CRP") levels (See Table 12). Serum CRP is abiochemical surrogate for the presence and progress of cancer cachexia,and shows a strong positive correlation. (Falconer, J. S. et al., Cancer1995, 75:2077). Patients with serum CRP levels >10 mg/L are franklycachectic. The mean CRP level at baseline was 31.5 and this dropped toabout 10 after 3 weeks on the experimental formula of the invention.Thus, the invention improves cachexia in pancreatic cancer patients.

                  TABLE 12                                                        ______________________________________                                        Patients' Lean Body Mass and CRP                                                             % Lean                                                               % Lean   Body                                                                 Body     Mass     Change in %                                                                           Baseline                                                                             CRP after                                    Mass at  after    Lean Body                                                                             CRP    3 week trial                           Patient                                                                             Baseline trial    Mass    mg/L   mg/L                                   ______________________________________                                        1     79.4     82.9     3.5     69     <10                                    2     85.6     na       na      81     na                                     3     84       92.2     8.2     27     <10                                    4     85.6     86.3     0.7     <10    <10                                    5     73.7     75       1.3     <10    <10                                    6     79.7     80.7     1       63     <10                                    7     90.2     91.9     1.7     <10     10                                    8     81.4     80.1     -1.3    <10    <10                                    9     82.6     na       na      25     na                                     10    86.9     na       na      <10    na                                     Mean  82.9     84.2     2.1     31.5    10*                                   ______________________________________                                         *CRP values read as <10 are assumed to be 10 for calculation of mean     

The present invention is not to be limited to the scope by the specificembodiments described herein. Indeed, various modifications of theinvention in addition to those described herein will become apparent tothose skilled in the art from the foregoing description. Suchmodifications are intended to fall within the scope of the appendedclaims.

Various publications and patents are cited herein, the disclosures ofwhich are incorporated by reference in their entireties.

We claim:
 1. A liquid nutritional composition comprising:(a) at least 1000 mg per liter of ω-3 fatty acids, wherein the weight ratio of ω-6 fatty acids to ω-3 fatty acids is from about 0.1 to about 1.0; (b) at least 50 grams per liter of a source of amino-nitrogen, wherein 15 to 50% by weight of the amino-nitrogen is branched-chain amino acids, and wherein tryptophan is present in an amount less than about 5.0% by weight of the total amino-nitrogen, and; (c) at least 1 gram per liter of an antioxidant system comprising beta-carotene, vitamin C, vitamin E and selenium.
 2. The composition according to claim 1 in which said ω-3 fatty acids are present in a quantity of about 1.0 gram to about 100 grams per liter.
 3. The composition according to claim 1 in which said ω-3 fatty acids are present in a quantity of about 5.0 grams to about 100 grams per liter.
 4. The composition according to claim 1 in which said ω-3 fatty acids are present in a quantity of about 5.0 grams to about 10.0 grams per liter.
 5. The composition according to any one of claims 2-4 in which 15% to 25% by weight of the amino-nitrogen is branched-chain amino acids.
 6. The composition claim 5 in which said tryptophan is present in an amount of less than 3.0% by weight a nitrogen.
 7. A liquid nutritional composition comprising:a) at least 1000 mg per liter of ω-3 fatty acids, wherein the weight ratio of ω-6 fatty acids to ω-3 fatty acids is about 0.1 to about 1.0; (b) at least 50 grams per liter of a source of amino-nitrogen, wherein 15 to 50% by weight of the amino-nitrogen is branched-chain amino acids, and wherein tryptophan is present in an amount less than about 5.0% by weight of the total amino-nitrogen, and; c) an antioxidant component comprising about 2,500 to about 6,500 micrograms per liter of beta-carotene, about 250 to about 1,000 milligrams per liter of vitamin C, about 100 to about 500 I.U. per liter of vitamin E, and about 75 to about 125 micrograms per liter of selenium.
 8. The composition according to claim 7 in which said ω-3 fatty acids are present in a quantity of about 1.0 gm to about 100 grams per liter.
 9. The composition according to claim 7 in which said ω-3 fatty acids are present in a quantity of about 5.0 grams to about 100 grams per liter.
 10. The composition according to claim 7 in which said ω-3 fatty acids are present in a quantity of about 5.0 grams to about 10.0 grams per liter.
 11. The composition according to any one of claims 7-10 in which 15% to 25% by weight of the amino-nitrogen is branched-chain amino acids.
 12. The composition according to claim 11 in which said tryptophan is present in an amount of less than 3.0% by weight of the total amino-nitrogen.
 13. A liquid nutritional composition comprising:a) optionally at least 50 grams per liter of a source of amino-nitrogen, wherein 15 to 50% by weight of the amino-nitrogen is branched-chain amino acids, and wherein tryptophan is present in an amount less than about 5.0% by weight of the total amino-nitrogen; b) an antioxidant component comprising about 2,500 to about 6,500 micrograms per liter of beta-carotene, about 250 to about 1,000 milligrams per liter of vitamin C, about 100 to about 500 I.U. per liter of vitamin E, and about 75 to about 125 microgram per liter of selenium, and; c) an oil blend further comprising 5-40 wt. % canola oil, 10-50 wt. % medium chain triglyceride oil, 25-80 wt. % fish oil, 3-30 wt. % soybean oil, and 2-6 wt. % soy lecithin.
 14. The liquid nutritional according to claim 13 in which said oil blend further comprises 9.3 wt. % canola oil, 16.2 wt. % medium chain triglyceride oil, 65 wt. % fish oil, 5.5 wt. % soybean oil, and 4.0 wt. % soy lecithin.
 15. A liquid nutritional composition comprising:a) an antioxidant component comprising about 2,500 to about 6,500 micrograms per liter of beta-carotene, about 250 to about 1,000 milligrams per liter of vitamin C, about 100 to about 500 I.U. per liter of vitamin E, and about 75 to about 125 microgram per liter of selenium, and; b) at least 1000 mg per liter of ω-3 fatty acids, wherein the weight ratio of ω-6 fatty acids to ω-3 fatty acids is about 0.1 to about 1.0.
 16. The composition according to claim 15 in which said ω-3 fatty acids are present in a quantity of about 1.0 gm to about 100 grams per liter.
 17. The composition according to claim 15 in which said ω-3 fatty acids are present in a quantity of about 5.0 grams to about 100 grams per liter.
 18. The composition according to claim 15 in which said ω-3 fatty acids are present in a quantity of about 5.0 grams to about 10.0 grams per liter.
 19. A liquid nutritional composition comprising:a) at least 50 grams per liter of a source of amino-nitrogen, wherein 15 to 50% by weight of the amino-nitrogen is branched-chain amino acids, and wherein tryptophan is present in an amount less than about 5.0% by weight of the total amino-nitrogen; b) an antioxidant component comprising about 2,500 to about 6,500 micrograms per liter of beta-carotene, about 250 to about 1,000 milligrams per liter of vitamin C, about 100 to about 500 I.U. per liter of vitamin E, and about 75 to about 125 microgram per liter of selenium, and; c) at least 4.47 grams of eicosapentaenoic acid per liter.
 20. A liquid nutritional composition comprising:a) an antioxidant component comprising about 2,500 to about 6,500 micrograms per liter of beta-carotene, about 250 to about 1,000 milligrams per liter of vitamin C, about 100 to about 500 I.U. per liter of vitamin E, and about 75 to about 125 microgram per liter of selenium, and; b) at least 4.47 grams of eicosapentaenoic acid per liter. 